JP6241956B2 - Ketone bodies and ketone body esters for maintaining or improving muscle power output - Google Patents
Ketone bodies and ketone body esters for maintaining or improving muscle power output Download PDFInfo
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- JP6241956B2 JP6241956B2 JP2015503897A JP2015503897A JP6241956B2 JP 6241956 B2 JP6241956 B2 JP 6241956B2 JP 2015503897 A JP2015503897 A JP 2015503897A JP 2015503897 A JP2015503897 A JP 2015503897A JP 6241956 B2 JP6241956 B2 JP 6241956B2
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- Prior art keywords
- ketone
- composition
- hydroxybutyric acid
- power output
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/06—Anabolic agents
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Description
本発明は、筋パワー出力を維持又は改善するためのケトン体及びケトン体エステル並びに筋パワー出力を維持又は改善するための組成物に関する。特に、本発明は、筋パワー出力を維持又は改善するためのヒドロキシ酪酸(hydroxybutyrate)エステルであって、対象の血漿内で循環するケトン体濃度を上昇させるヒドロキシ酪酸エステル、特に(R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオールモノエステルに関する。 The present invention relates to ketone bodies and ketone body esters for maintaining or improving muscle power output, and compositions for maintaining or improving muscle power output. In particular, the present invention is a hydroxybutyrate ester for maintaining or improving muscle power output, which increases the concentration of ketone bodies circulating in the plasma of a subject, particularly (R) -3- Hydroxybutyric acid-R-1,3-butanediol monoester.
ケトン体は、体内で脂肪酸レベルが上昇すると産生され、エネルギーのため体によって代謝される。ケトン体は対象の血漿内で循環する遊離脂肪酸のレベルを下げるのに適していると、またケトン体の摂取は、認知能力の増強並びに心血管状態、糖尿病の治療及びミトコンドリア機能不全障害の治療を含めた種々の臨床上の利点、並びに筋肉疲労及び筋肉障害の治療における臨床上の利点をもたらし得ることが開示されている。
WO2004/108740は、ケトン体の血中濃度の上昇に有効な(R)-3-ヒドロキシ酪酸誘導体を含有する化合物及び組成物並びに該化合物、特に多量体及び組成物を栄養補助食品として又は医学的状態を治療するために使用する方法を開示している。(R)-3-ヒドロキシ酪酸誘導体及びこれらの誘導体を含む組成物は、アセト酢酸(acetoacetate)及び(R)-3-ヒドロキシ酪酸等のケトン体への前駆物質として働くことができ、対象に投与されると、ケトン体の血中濃度上昇をもたらすと言われている。
WO2004/105742は、筋肉、特に心筋又は骨格筋の障害若しくは疲労又はミトコンドリア機能不全の治療又は予防のための、対象の血漿内で循環する遊離脂肪酸を減らす化合物、例えばケトン体、サリチル酸、ニコチン酸、トリアゾリジンジオン及びフィブラートの使用を開示している。水と、糖炭水化物と、血漿内で循環する遊離脂肪酸を減らす化合物とを含んでなる、運動中又は運動後の水分補給のための液体組成物も開示されている。
Ketone bodies are produced when fatty acid levels rise in the body and are metabolized by the body for energy. Ketone bodies are suitable for lowering the level of free fatty acids circulating in a subject's plasma, and ingestion of ketone bodies can enhance cognitive performance and treat cardiovascular conditions, diabetes and mitochondrial dysfunction. It has been disclosed that various clinical benefits can be provided, as well as clinical benefits in the treatment of muscle fatigue and disorders.
WO2004 / 108740 describes compounds and compositions containing (R) -3-hydroxybutyric acid derivatives that are effective for increasing blood levels of ketone bodies, and compounds, especially multimers and compositions as dietary supplements or medical Disclosed are methods for use in treating a condition. (R) -3-Hydroxybutyric acid derivatives and compositions comprising these derivatives can act as precursors to ketone bodies such as acetoacetate and (R) -3-hydroxybutyric acid and are administered to subjects If done, it is said to cause an increase in the blood level of ketone bodies.
WO2004 / 105742 describes compounds that reduce free fatty acids circulating in the plasma of a subject, such as ketone bodies, salicylic acid, nicotinic acid, for the treatment or prevention of muscle or in particular myocardial or skeletal muscle disorders or fatigue or mitochondrial dysfunction Disclose the use of triazolidinedione and fibrate. Also disclosed is a liquid composition for hydration during or after exercise, comprising water, a sugar carbohydrate, and a compound that reduces free fatty acids circulating in plasma.
ケトン体の特定の治療上その他の利点は知られており、ケトンは患者又は対象の遊離脂肪酸レベルを下げることができる。我々は今や驚くべきことにケトン体及びケトン体エステルが筋パワー出力を維持又は改善できることを見い出した。 Certain therapeutic other benefits of ketone bodies are known and ketones can lower the level of free fatty acids in a patient or subject. We have now surprisingly found that ketone bodies and ketone body esters can maintain or improve muscle power output.
第一態様では、本発明は、筋パワー出力の維持又は改善に用いるためのケトン体又はケトン体エステルを提供する。
本明細書で使用する場合、用語「ケトン」、「ケトン体」又は「ケトン体(複数)」は、ケトン又はケトン体前駆物質である化合物又は種、すなわち、ケトンへの前駆物質であり、変換又は代謝されてケトンになり得る化合物又は種を意味する。
本発明は、骨格筋パワー出力を維持又は改善する。本発明は、他のタイプの筋肉、例えば心筋のパワー出力の維持又は改善をもたらすこともできる。筋肉のパワー出力は本明細書の実施例で述べる方法に従って測定可能である。
本発明は、健康人、例えば血液検査をしたときに身体能力に影響し得る医学的原因、例えば鉄欠乏、ヘモグロビン(Hb)、電解質、白血球数(WCC)及び空腹時血糖を示さない人の骨格筋パワー出力を維持又は改善するのに特に有用である。本発明は、身体が元気な対象、特に高レベルのフィットネスを有する対象、例えばアスリート及び軍人、特に既に高レベルのパワー出力からの改善をさらになし得るエリートアスリートの筋能力の維持又は改善に特に有用である。
本発明は好適には本明細書の実施例で述べるように対照試験で測定すると、プラセボに対して少なくとも0.25%、好ましくは少なくとも0.5%、さらに好ましくは少なくとも1%のパワー出力の改善をもたらす。
好ましい実施形態の本発明は、本明細書の実施例で述べるように対照試験で測定すると、プラセボに対して少なくとも1ワット、さらに好ましくは少なくとも2ワット、望ましくは少なくとも5ワットのパワー出力の増加をもたらす。パワー出力の増加は好適には対照試験の30分後、さらに好ましくは15分後に達成される。
In a first aspect, the present invention provides a ketone body or a ketone body ester for use in maintaining or improving muscle power output.
As used herein, the terms “ketone”, “ketone body” or “ketone body (s)” are compounds or species that are ketones or ketone body precursors, ie, precursors to ketones, conversion Or a compound or species that can be metabolized to a ketone.
The present invention maintains or improves skeletal muscle power output. The present invention can also result in maintaining or improving the power output of other types of muscle, such as the myocardium. Muscle power output can be measured according to the methods described in the examples herein.
The present invention relates to the skeleton of healthy individuals, such as those who do not exhibit medical causes that may affect physical performance when blood tests are performed, such as iron deficiency, hemoglobin (Hb), electrolytes, white blood cell count (WCC) and fasting blood glucose. It is particularly useful for maintaining or improving muscle power output. The present invention is particularly useful for maintaining or improving the muscular capacity of healthy subjects, particularly subjects with high levels of fitness, such as athletes and military personnel, especially elite athletes who can further improve from already high levels of power output It is.
The present invention preferably results in an improvement in power output of at least 0.25%, preferably at least 0.5%, more preferably at least 1% relative to placebo, as measured in a control test as described in the examples herein.
The preferred embodiment of the present invention provides an increase in power output of at least 1 watt, more preferably at least 2 watts, and desirably at least 5 watts relative to placebo, as measured in a control test as described in the Examples herein. Bring. The increase in power output is preferably achieved after 30 minutes, more preferably 15 minutes after the control test.
本発明では、いずれのケトン体若しくはケトン体エステル又は人体内でケトンを与えるいずれの化合物を利用してもよい。好ましくは、ケトンエステル、特にケトンモノエステルを利用する。適切なケトン体又は生体内でケトン体を与える化合物の例としては、ヒドロキシ酪酸とその誘導体、例えば(R)-3-ヒドロキシ酪酸を含めたヒドロキシ酪酸のエステルとその誘導体、アルコール及び1つ以上のフリーのヒドロキシル基を含む化合物から誘導されるエステルを含めた(R)-3-ヒドロキシ酪酸及び(R)-3-ヒドロキシ酪酸の多量体のエステルが挙げられる。適切なアルコールとしては、ブタンジオール、特に、ブタン-1,3-ジオール、アルトロース、アラビノース、デキストロース、エリトロース、フルクトース、ガラクトース、グルコース、グリセロール、グロース、イドース、ラクトース、リキソース、マンノース、リビトール、リボース、リブロース、スクロース、タロース、トレオース、キシリトール、キシロースが挙げられる。
ケトン体の非経口投与は、例えばUS-A-6,136,862から知られているが、必要とされ得る塩又は酸の量のため非経口投与又は注射では実現できないであろう、循環するケトン体レベルを迅速に上昇させるためには経口投与が望ましい。経口投与の他の利点には、非経口投与又は注射器具を必要としない便利さ、投与計画への対象のコンプライアンス及び針への嫌悪の可能性がある対象のコンプライアンス並びに特に比較的短い間隔内で複数用量のケトンを摂取すべきであり、かつ用量が消費されて運動能力の改善がもたらされる場合の投与の容易さがある。
摂取されると、ケトン体は、生理作用を与えるために腸から血液へ流れる必要がある。血液中のケトンの濃度は腸から血液へのケトンの取り込みレベルによって決まる。比較的低い取り込みのケトンでは、より高いレベルのケトンが腸内で必要であろう。これは同様にケトンの所定の血中濃度を達成するために摂取すべきケトンの量を増やす必要がある。
我々は、(R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオールモノエステルが驚くべきことに嫌悪感のない味がすることを見い出した。さらに、このモノエステルは驚くべきことに高レベルの取り込みをもたらし、それによって経口用量を消費すると、ヒドロキシ酪酸の高い血中濃度を達成することができる。
さらなる態様では、本発明は、対象の筋パワー出力の維持又は改善に用いるための(R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオールモノエステルを提供する。
特に好ましい実施形態では、ケトンは、特にエナンチオマー的に富化された形態の3-ヒドロキシブチル-(R)-3-ヒドロキシ酪酸を含む。
In the present invention, any ketone body or ketone body ester or any compound that provides a ketone in the human body may be used. Preferably, ketone esters, especially ketone monoesters are utilized. Examples of suitable ketone bodies or compounds that provide ketone bodies in vivo include hydroxybutyric acid and its derivatives, such as esters and derivatives of hydroxybutyric acid, including (R) -3-hydroxybutyric acid, alcohols and one or more Multimeric esters of (R) -3-hydroxybutyric acid and (R) -3-hydroxybutyric acid, including esters derived from compounds containing free hydroxyl groups. Suitable alcohols include butanediol, especially butane-1,3-diol, altrose, arabinose, dextrose, erythrose, fructose, galactose, glucose, glycerol, growth, idose, lactose, lyxose, mannose, ribitol, ribose, Examples include ribulose, sucrose, talose, threose, xylitol, and xylose.
Parenteral administration of ketone bodies is known, for example, from US-A-6,136,862, but circulates ketone body levels that would not be feasible with parenteral administration or injection due to the amount of salt or acid that may be required. Oral administration is desirable for rapid elevation. Other advantages of oral administration include the convenience of not requiring parenteral administration or injection devices, subject compliance to dosing regimens and subject compliance with potential needle aversion, and especially within relatively short intervals. There is ease of administration when multiple doses of ketones should be taken and doses are consumed resulting in improved exercise capacity.
When ingested, the ketone bodies need to flow from the intestines to the blood to provide physiological effects. The concentration of ketones in the blood depends on the level of ketone uptake from the intestine into the blood. With relatively low uptake ketones, higher levels of ketones may be required in the intestine. This also requires increasing the amount of ketone to be consumed to achieve a given blood level of ketone.
We have found that (R) -3-hydroxybutyric acid-R-1,3-butanediol monoester has a surprisingly disgusting taste. In addition, this monoester surprisingly provides a high level of uptake, whereby high blood concentrations of hydroxybutyric acid can be achieved when an oral dose is consumed.
In a further aspect, the present invention provides (R) -3-hydroxybutyric acid-R-1,3-butanediol monoester for use in maintaining or improving muscle power output in a subject.
In a particularly preferred embodiment, the ketone comprises 3-hydroxybutyl- (R) -3-hydroxybutyric acid, particularly in an enantiomerically enriched form.
本発明は、0.5g/kg(対象の体重)で対象にモノエステルを経口投与した後に血中(R)-3-ヒドロキシ酪酸濃度を少なくとも1mM、好ましくは少なくとも2mM、特に3mMに上昇させるのに使用するためのケトン体又はケトン体エステル、好ましくは(R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオールモノエステルをも提供する。1g/kg(対象の体重)の用量のモノエステルを経口投与すると、血中(R)-3-ヒドロキシ酪酸濃度は好適には少なくとも4mM、好ましくは少なくとも5mM、特に6mMである。1.5g/kg(対象の体重)の用量のモノエステルを経口投与すると、血中(R)-3-ヒドロキシ酪酸濃度は好適には少なくとも7mM、好ましくは少なくとも8mM、特に少なくとも9mMである。経口投与は複数用量で行なってよいが、単一用量で行なうのが好ましい。
3-ヒドロキシブチル-(R)-3-ヒドロキシ酪酸は他のケトン及び他の送達形態、例えば非経口を用いるよりずっと少ない量の物質の経口摂取で血中ヒドロキシ酪酸濃度の大きな上昇を達成できるので特に有利である。従って身体運動前又は身体運動中に該物質を摂取する対象は、大量又は苦味若しくは別の嫌悪風味に起因する身体的不快感のリスクなしで生理学的に有益な反応を与えるために十分なケトンをずっと容易に摂取することができる。また高レベルの血中(R)-3-ヒドロキシ酪酸濃度は、上昇した濃度を他のケトンより長い時間維持し、それによって、上昇したレベルを維持するために必要とされるさらなる用量の投与頻度が他のケトンより少ない。
グリセロールモノエステル及びジエステルも嫌悪感のない味がし、血中(R)-3-ヒドロキシ酪酸の上昇をもたらす。本発明は、対象の筋パワー出力の維持又は改善に用いるための(R)-3-ヒドロキシ酪酸グリセロールモノエステル又はジエステルを提供する。モノエステルは好適には1位でエステル化している。ジエステルは好適には1位及び3位でエステル化している。(R)-3-ヒドロキシ酪酸は単量体である。
(R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオールモノエステル、(R)-3-ヒドロキシ酪酸グリセロールモノエステル又はジエステルは単独で、又は互いに組み合わせて利用可能であり、或いは他のケトン体又はケトン体前駆物質をいずれの他の該ケトン体より少ない量で、好ましくはいずれの該他のケトン体より多い量で含んでよい。特に好ましい実施形態では、(R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオールモノエステルが本発明の組成物に存在する唯一のケトン体又はケトン体前駆物質である。
The present invention is intended to increase blood (R) -3-hydroxybutyric acid concentration to at least 1 mM, preferably at least 2 mM, especially 3 mM after oral administration of monoester to a subject at 0.5 g / kg (body weight). Also provided are ketone bodies or ketone body esters, preferably (R) -3-hydroxybutyric acid-R-1,3-butanediol monoester for use. When a monoester dose of 1 g / kg (subject's body weight) is orally administered, the blood (R) -3-hydroxybutyric acid concentration is suitably at least 4 mM, preferably at least 5 mM, especially 6 mM. When a monoester dose of 1.5 g / kg (body weight of the subject) is administered orally, the blood (R) -3-hydroxybutyric acid concentration is suitably at least 7 mM, preferably at least 8 mM, in particular at least 9 mM. Oral administration may be done in multiple doses, but preferably in a single dose.
Since 3-hydroxybutyl- (R) -3-hydroxybutyric acid can achieve a significant increase in blood hydroxybutyric acid levels with ingestion of much lower amounts of substances than other ketones and other delivery forms such as parenteral use Particularly advantageous. Thus, subjects who take the substance before or during physical exercise should have enough ketones to provide a physiologically beneficial response without the risk of physical discomfort due to high amounts or bitterness or another disgusting taste. It can be taken much more easily. High levels of blood (R) -3-hydroxybutyric acid also maintain the elevated concentration for longer periods of time than other ketones, thereby increasing the frequency of additional doses required to maintain the elevated levels. Is less than other ketones.
Glycerol monoesters and diesters also taste unpleasant and lead to an increase in blood (R) -3-hydroxybutyric acid. The present invention provides (R) -3-hydroxybutyric acid glycerol monoester or diester for use in maintaining or improving the muscle power output of a subject. The monoester is preferably esterified at the 1-position. The diester is preferably esterified at the 1- and 3-positions. (R) -3-hydroxybutyric acid is a monomer.
(R) -3-hydroxybutyric acid-R-1,3-butanediol monoester, (R) -3-hydroxybutyric acid glycerol monoester or diester may be used alone or in combination with each other, or other ketones Body or ketone body precursor may be included in an amount less than any other ketone body, preferably in an amount greater than any other ketone body. In a particularly preferred embodiment, (R) -3-hydroxybutyric acid-R-1,3-butanediol monoester is the only ketone body or ketone body precursor present in the composition of the present invention.
さらなる実施形態では、本発明は、対象の筋パワー出力の維持又は改善に用いるための、ケトン体又はケトン体エステルを含んでなる組成物を提供する。
好適には、組成物は、水と、ケトン体又はケトン体エステルとを含む。好ましくは、組成物は、ケトン体又はケトン体前駆物質と、調味料とを含み、任意にタンパク質、炭水化物、糖、脂肪、繊維、ビタミン及びミネラルの1種以上を含んでよい。
異なるケトン体又はケトン体エステルは異なるレベルの取り込みを有する。我々は、ケトンエステルはケトンの他の形態、例えばトリオリド及び多量体より効率的に消化されることを見い出した。消化の相対的容易さから利益を得るため、ケトン体は好ましくはケトンエステルを含む。実益として、血漿ケトンの所定レベルを達成するため、組成物は、別のケトン体を使用する予定の場合より低いレベルのケトンエステルを含有し得るので、運動しながらの物質の摂取において対象が不安又は不快感なしで確実に筋パワー送達を改善できるように運動前又は運動中の素早い摂取と快適さを可能にする。これは運動レベルが激しいか又は長期に及ぶ場合に特に有益である。有利には、このことは対象が運動の直前又は運動中にケトン体又はケトン体エステルの用量を摂取して筋パワー送達を維持又は改善できるようにする。
好ましくは、ケトン体エステルは部分エステル、すなわちヒドロキシル基の一部のみがエステル化しているポリオールを含む。モノエステルが特に好ましく、2つ以上のヒドロキシル基がエステル化しているが、エステル化したヒドロキシル基は「β関係」でない、すなわちこれらのヒドロキシル基は隣接炭素原子に結合していないエステルが好ましい。
ヒドロキシ酪酸エステル、特に部分エステル、例えばヒドロキシ酪酸ブタン-1,3-ジオールモノエステルは驚くべきレベルの取り込みをもたらし、そのため筋パワー出力の維持又は改善を対象に与えるのに特に適している。
好適にはケトン体又はケトン体エステルは1日に体重1kg当たり少なくとも100mgのケトンのレベルで摂取される。ケトンの血漿レベルは個体の体重によって決まるであろう。我々は、体重1kg当たり少なくとも300mgのケトンのケトン用量が約1.5mMのケトンの血漿濃度を与えることを見い出した。望ましくは、ケトン体又はケトン体エステルは、少なくとも0.1mM、好ましくは少なくとも0.2mM、さらに好ましくは少なくとも1mM、最適には少なくとも2mMの血漿ケトンレベルを与えるのに十分なレベルで摂取される。好適にはケトン体又はケトン体エステルは、血漿ケトンレベルが20mMを超えない、好適には10mM又は8mMを超えない、また5mMを超えないかもしれないようなレベルで摂取される。
ケトンの血漿レベルは市販の試験キット、例えばBayer, Inc.から入手可能なKetostixで測定可能である。
In a further embodiment, the present invention provides a composition comprising a ketone body or a ketone body ester for use in maintaining or improving a subject's muscle power output.
Preferably, the composition comprises water and a ketone body or ketone body ester. Preferably, the composition comprises a ketone body or ketone body precursor and a seasoning, and may optionally comprise one or more of proteins, carbohydrates, sugars, fats, fiber, vitamins and minerals.
Different ketone bodies or ketone body esters have different levels of uptake. We have found that ketone esters are more efficiently digested than other forms of ketones such as triolides and multimers. In order to benefit from the relative ease of digestion, the ketone body preferably comprises a ketone ester. In practice, in order to achieve a predetermined level of plasma ketone, the composition may contain a lower level of ketone ester than would be expected if another ketone body was to be used, so the subject is concerned about taking the substance while exercising. Or allow quick ingestion and comfort before or during exercise to ensure improved muscle power delivery without discomfort. This is particularly beneficial when the exercise level is intense or prolonged. Advantageously, this allows the subject to take a dose of ketone bodies or ketone body esters immediately before or during exercise to maintain or improve muscle power delivery.
Preferably, the ketone ester includes a partial ester, that is, a polyol in which only a part of the hydroxyl group is esterified. Monoesters are particularly preferred, and two or more hydroxyl groups are esterified, but esterified hydroxyl groups are not “β related”, ie, esters in which these hydroxyl groups are not bonded to adjacent carbon atoms are preferred.
Hydroxybutyric acid esters, particularly partial esters, such as hydroxybutyric acid butane-1,3-diol monoester, provide surprising levels of uptake and are therefore particularly suitable for providing a subject with maintenance or improvement of muscle power output.
Preferably, the ketone body or ketone body ester is taken at a level of at least 100 mg ketone / kg body weight per day. The plasma level of ketones will depend on the weight of the individual. We have found that a ketone dose of at least 300 mg ketone / kg body weight gives a plasma concentration of about 1.5 mM ketone. Desirably, the ketone body or ketone body ester is ingested at a level sufficient to provide a plasma ketone level of at least 0.1 mM, preferably at least 0.2 mM, more preferably at least 1 mM, and optimally at least 2 mM. Preferably, the ketone body or ketone body ester is taken at a level such that the plasma ketone level does not exceed 20 mM, preferably does not exceed 10 mM or 8 mM, and may not exceed 5 mM.
Plasma levels of ketones can be measured with commercially available test kits such as Ketostix available from Bayer, Inc.
従って好ましい実施形態では、本発明は、対象の筋パワー出力の維持又は改善に用いるためのヒドロキシ酪酸エステル又は部分エステル、例えば(R)-3-ヒドロキシ酪酸ブタン-1,3-ジオールモノエステルを提供する。
さらに好ましい実施形態は、対象の筋パワー出力の維持又は改善に用いるためのヒドロキシ酪酸エステル又は部分エステル、例えば(R)-3-ヒドロキシ酪酸ブタン-1,3-ジオールモノエステルであって、対象の血液中のヒドロキシ酪酸及びアセト酢酸の循環レベルが0.1〜20、好ましくは0.5〜10、最適には1より大きく5mMまでである場合のものを提供する。
本発明は、対象の筋パワー出力の維持又は改善におけるケトン体若しくはケトン体エステル又はケトン体若しくはケトン体エステルを含有する組成物の使用をも提供する。好ましくは対象の血液中のヒドロキシ酪酸及びアセト酢酸のレベルは0.1〜20、好ましくは0.5〜10、最適には1より大きく5mMまでである。
ケトン体及びケトン体エステルは相対的にまずい。我々は、(R)-3-ヒドロキシ酪酸のエステル、特に部分エステルは他のケトン体エステルよりまずくなく、所望効果を与えるのに十分に高いレベルでの対象への所望ケトン体の適正な送達を実現するのに役立つことを見い出した。
ヒドロキシ酪酸エステルを含有するケトン体と、調味料、特に苦味調味料とを含む成分の特定の組み合わせを選択することによって、ケトンを所望レベルで血漿に通せるようにする感覚刺激的に許容できる(organoleptically acceptable)組成物を得ることができ、この組成物は筋パワー出力の改善をもたらす。
「感覚刺激的に許容できる」とは、組成物が味、色、感じ及び匂いの許容できる感覚特性を持たなければならないことを意味する。組成物が感覚刺激的に許容性かそうでないかは、個人的嗜好を含めた外部要因を考慮する、使用者による主観的評価であり、盲検試験により決定可能である。
Accordingly, in a preferred embodiment, the present invention provides a hydroxybutyric acid ester or partial ester, such as (R) -3-hydroxybutyric acid butane-1,3-diol monoester, for use in maintaining or improving a subject's muscle power output To do.
A further preferred embodiment is a hydroxybutyric acid ester or partial ester, such as (R) -3-hydroxybutyric acid butane-1,3-diol monoester, for use in maintaining or improving a subject's muscle power output, comprising: Provided when the circulating level of hydroxybutyric acid and acetoacetic acid in the blood is 0.1-20, preferably 0.5-10, optimally greater than 1 and up to 5 mM.
The present invention also provides the use of a ketone body or ketone body ester or a composition containing a ketone body or ketone body ester in maintaining or improving the muscle power output of a subject. Preferably the level of hydroxybutyric acid and acetoacetic acid in the blood of the subject is 0.1-20, preferably 0.5-10, optimally greater than 1 and up to 5 mM.
Ketone bodies and ketone body esters are relatively poor. We have found that the esters of (R) -3-hydroxybutyric acid, especially partial esters, are less likely than other ketone esters and provide adequate delivery of the desired ketone to the subject at a level sufficiently high to provide the desired effect. I found it useful to realize.
By selecting a specific combination of ingredients comprising a ketone body containing a hydroxybutyric acid ester and a seasoning, particularly a bitter seasoning, it can be sensorially acceptable to allow the ketone to pass through the plasma at the desired level ( organoleptically acceptable) compositions can be obtained, which results in improved muscle power output.
By “sensory stimuli acceptable” is meant that the composition must have acceptable sensory properties of taste, color, feel and smell. Whether the composition is sensorially tolerable or not is a subjective assessment by the user, taking into account external factors including personal preferences, and can be determined by blinded trials.
本発明はさらに、用量レジメでのケトン体又はケトン体エステルの投与によって筋パワー出力を維持又は改善する方法を含む。この方法では、レジメは、少なくとも1つの用量でケトン体又はケトン体エステルを投与して血液中のヒドロキシ酪酸及びアセト酢酸の循環レベルを0.1又は1〜20、好ましくは0.5又は1〜10、最適には1より大きく8mMまで又は1〜5mMにする工程を含み、少なくとも1つの用量は、対象の体重1kg当たり少なくとも100mg、好ましくは少なくとも300〜750mg/kgの量のケトン体又はケトン体エステルを含む。
ケトン体又はケトン体エステルを固体形態の組成物として与える場合、組成物中のケトン体又はケトン体エステルのレベルは好適には、ヒドロキシ酪酸エステルを含めたケトン体を組成物の少なくとも5質量%、さらに好ましくは少なくとも10質量%かつ95質量%まで含む。例えば組成物が液体組成物を作製するために液体と共に使用することを意図した乾燥粉末である場合、乾燥組成物の15〜30質量%のレベルが適切であり得るが、固体棒又は製品形態は好適には組成物の30〜95%、特に50〜95質量%含む。組成物が液体形態の場合、組成物は好適には液体組成物の少なくとも1質量%、例えば3〜40質量%のレベルでケトン体を含むが、所望の血中ケトンレベルに到達するために組成物が単一用量としてか又は複数の少用量で摂取することを意図されるかどうかによっては、組成物の例えば50質量%までのより高いレベルであってもよい。
液体形態の組成物は、好適には適切な液体、例えば水、果汁又はミルクで希釈される乾燥組成物を好ましくは1:1〜1:10、さらに好ましくは1:3〜1:7の乾燥組成物対液体の比で含む。感覚刺激的に許容できるケトン体のレベルは、組成物の正確な組成及びその形態並びに他成分のマスキング効果に応じて異なるであろう。
組成物は固体、例えば、粉末、錠剤、棒、菓子製品又は顆粒であってよく、固体経口投与形として用いることを意図してよい。別の実施形態では、固体組成物を使用前に液体、好ましくは水、果実ベース液体又は乳製品、例えばミルク及びヨーグルトと混合して使用者に液体飲料を与えてよい。組成物の担体としてはミルク、果汁及び水が特に好ましい。所望により、組成物をすぐに消費できる形態の液体製品として又は使用時に希釈するのに適した濃縮物若しくはペーストとして提供してよい。液体組成物と共に使用するための希釈剤はミルク、果汁又は水が好ましい。
The invention further includes a method of maintaining or improving muscle power output by administration of ketone bodies or ketone body esters in a dosage regime. In this method, the regimen is administered with a ketone body or ketone body ester in at least one dose to achieve a circulating level of hydroxybutyric acid and acetoacetic acid in the blood of 0.1 or 1 to 20, preferably 0.5 or 1 to 10, optimally. Comprises a step of greater than 1 to 8 mM or 1 to 5 mM, wherein at least one dose comprises a ketone body or a ketone body ester in an amount of at least 100 mg, preferably at least 300 to 750 mg / kg body weight of the subject.
When the ketone body or ketone body ester is provided as a composition in solid form, the level of the ketone body or ketone body ester in the composition is preferably at least 5% by weight of the ketone body including the hydroxybutyric acid ester, More preferably, it contains at least 10% by mass and 95% by mass. For example, if the composition is a dry powder intended to be used with a liquid to make a liquid composition, a level of 15-30% by weight of the dry composition may be appropriate, but the solid bar or product form is Preferably it comprises 30-95%, in particular 50-95% by weight of the composition. When the composition is in liquid form, the composition preferably comprises a ketone body at a level of at least 1%, such as 3-40% by weight of the liquid composition, but is composition to reach the desired blood ketone level. Depending on whether the product is intended to be taken as a single dose or in multiple smaller doses, it may be at a higher level, eg up to 50% by weight of the composition.
The composition in liquid form is preferably a dry composition diluted with an appropriate liquid, such as water, fruit juice or milk, preferably 1: 1 to 1:10, more preferably 1: 3 to 1: 7. Included in a composition to liquid ratio. The level of ketone bodies that are perceptually acceptable will vary depending on the exact composition of the composition and its form as well as the masking effect of other components.
The composition may be a solid, such as a powder, tablet, stick, confectionery product or granule, and may be intended for use as a solid oral dosage form. In another embodiment, the solid composition may be mixed with a liquid, preferably water, a fruit-based liquid or a dairy product such as milk and yogurt prior to use to give the user a liquid beverage. Milk, fruit juice and water are particularly preferred as the carrier for the composition. If desired, the composition may be provided as a ready-to-consume liquid product or as a concentrate or paste suitable for dilution at the time of use. The diluent for use with the liquid composition is preferably milk, fruit juice or water.
組成物が固体形態の場合、組成物はさらに下記成分の1種以上を含んでよい：
−希釈剤、例えばラクトース、デキストロース、サッカロース、セルロース、トウモロコシデンプン又はジャガイモデンプン；
−潤沢剤、例えばシリカ、タルク、ステアリン酸、ステアリン酸マグネシウム若しくはステアリン酸カルシウム及び／又はポリエチレングリコール；
−結合剤、例えばデンプン、アラビアガム、ゼラチン、メチルセルロース、カルボキシメチルセルロース、又はポリビニルピロリドン；
−崩壊剤、例えばデンプン、アルギン酸、アルギン酸塩又はデンプングリコール酸ナトリウム；
−起泡剤；
−染料；
−甘味料；
−湿潤剤、例えばレシチン、ポリソルベート、硫酸ラウリル。
被包材料及びその使用量がヒトの安全な消費に適しているという条件で、組成物を被包形態で提供してもよい。しかしながら、被包は好ましくない。
本発明の組成物は、中鎖トリグリセリド(MCT)及び任意にそれらの関連脂肪酸を含有し得る。MCTは、炭素原子が5〜12の鎖長の脂肪酸を含む。MCTに富む食事が高い血中ケトンレベルをもたらすことは知られている。適切な中鎖トリグリセリドは、次式CH2R1-CH2R2-CH2R3（式中、R1、R2及びR3は、5〜12個の炭素原子を有する脂肪酸である）で表される。好ましくは、R1、R2及びR3が6炭素骨格(トリ-C6:0)を含有する脂肪酸であるMCTを利用する。これはトリ-C6:0 MCTは胃腸管によって非常に迅速に吸収されると報告されているからである。
MCTを利用する場合、好適には本発明の組成物は、i)ケトン体、好ましくはケトンモノエステル、さらに好ましくは(R)-3-ヒドロキシ酪酸モノエステル及びii)MCT、好ましくはトリ-C6:0 MCTを含む。
When the composition is in solid form, the composition may further comprise one or more of the following components:
-Diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch;
A lubricant, such as silica, talc, stearic acid, magnesium stearate or calcium stearate and / or polyethylene glycol;
-Binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone;
Disintegrants such as starch, alginic acid, alginate or sodium starch glycolate;
-Foaming agents;
-Dyes;
-Sweeteners;
-Wetting agents such as lecithin, polysorbate, lauryl sulfate.
The composition may be provided in an encapsulated form, provided that the encapsulating material and the amount used are suitable for human safe consumption. However, encapsulation is not preferred.
The compositions of the present invention may contain medium chain triglycerides (MCT) and optionally their related fatty acids. MCT contains fatty acids with chain lengths of 5 to 12 carbon atoms. It is known that a diet rich in MCTs results in high blood ketone levels. Suitable medium chain triglycerides are of the formula CH 2 R 1 —CH 2 R 2 —CH 2 R 3 where R 1 , R 2 and R 3 are fatty acids having 5 to 12 carbon atoms It is represented by Preferably, MCT is used in which R 1 , R 2 and R 3 are fatty acids containing a 6-carbon skeleton (tri-C6: 0). This is because tri-C6: 0 MCT has been reported to be absorbed very quickly by the gastrointestinal tract.
When utilizing MCT, suitably the composition of the invention comprises i) a ketone body, preferably a ketone monoester, more preferably (R) -3-hydroxybutyric acid monoester and ii) MCT, preferably tri-C6. : 0 Includes MCT.
本発明の組成物は、L-カルニチン又はL-カルニチンの誘導体を含んでもよい。L-カルニチンの誘導体の例としては、デカノイルカルニチン、ヘキサノイルカルニチン、カプロイルカルニチン、ラウロイルカルニチン、オクタノイルカルニチン、ステアロイルカルニチン、ミリストイルカルニチン、アセチル-L-カルニチン、O-アセチル-L-カルニチン、及びパルミトイル-L-カルニチンが挙げられる。カルニチンを利用する場合、好適には本発明の組成物は、i)ケトン体、好ましくはケトンモノエステル、さらに好ましくは(R)-3-ヒドロキシ酪酸モノエステル及びii)L-カルニチン又はL-カルニチンの誘導体を含む。
さらなる実施形態では、組成物は、i)ケトン体、好ましくはケトンモノエステル、さらに好ましくは(R)-3-ヒドロキシ酪酸モノエステル、ii)MCT、好ましくはトリ-C6:0 MCT又はトリ-C8:0 MCT及びiii) L-カルニチン又はL-カルニチンの誘導体を含む。
MCT及びL-カルニチン又はその誘導体を利用する場合、好適にはMCTをカルニチンと乳化させる。好ましくは10〜500gの乳化MCTを10〜2000mgのカルニチンと併用する。例えば50gのモノグリセリド及びジグリセリドと乳化した50gのMCT(95%トリC8:0)を500mgのL-カルニチンと併用する。
MCTは、ケトン体より多い量で存在してよいが、好ましくはケトン体のレベルはMCTのレベルより大きい。
The composition of the present invention may comprise L-carnitine or a derivative of L-carnitine. Examples of derivatives of L-carnitine include decanoyl carnitine, hexanoyl carnitine, caproyl carnitine, lauroyl carnitine, octanoyl carnitine, stearoyl carnitine, myristoyl carnitine, acetyl-L-carnitine, O-acetyl-L-carnitine, and Palmitoyl-L-carnitine is mentioned. When carnitine is utilized, suitably the composition of the invention comprises i) a ketone body, preferably a ketone monoester, more preferably (R) -3-hydroxybutyric acid monoester and ii) L-carnitine or L-carnitine. Derivatives thereof.
In a further embodiment, the composition comprises i) a ketone body, preferably a ketone monoester, more preferably (R) -3-hydroxybutyric acid monoester, ii) MCT, preferably tri-C6: 0 MCT or tri-C8. : 0 MCT and iii) L-carnitine or a derivative of L-carnitine.
When MCT and L-carnitine or a derivative thereof are used, MCT is preferably emulsified with carnitine. Preferably, 10 to 500 g of emulsified MCT is used in combination with 10 to 2000 mg of carnitine. For example, 50 g of MCT (95% Tri C8: 0) emulsified with 50 g of monoglyceride and diglyceride is used in combination with 500 mg of L-carnitine.
The MCT may be present in an amount greater than the ketone body, but preferably the ketone body level is greater than the MCT level.
組成物は固体組成物の形態又は液体組成物若しくはゲルの形態であってよい。組成物の適切な固体形態としては、棒又は使用時に液体、例えば水、ミルク若しくは果汁と混合するのに適した粉末が挙げられる。液体組成物の適切な形態としては、例えばシロップ、エマルション及び懸濁液が挙げられる。好適には、シロップの形態では、組成物はさらに担体として、例えば、サッカロース又はサッカロースとグリセリン及び／又はマンニトール及び／又はソルビトールを含有し得る。懸濁液又はエマルションの形態では、組成物は担体として、例えば、天然ガム、寒天、アルギン酸ナトリウム、ペクチン、メチルセルロース、カルボキシメチルセルロース又はポリビニルアルコールを含有し得る。
組成物は、食物製品、食物サプリメント、食事性サプリメント、機能性食品又は栄養補助食品又はその成分であり得る。
食物製品は、生物の体内で用いられて成長を持続し、損傷を修復し、生命プロセスを援助するか又はエネルギーを供給する1種以上の多量栄養素タンパク質、炭水化物及び脂肪で主に構成される食用物質である。食物製品は、ビタミン若しくはミネラル等の1種以上の微量栄養素、又は調味料及び着色料等の追加の食事性成分をも含有し得る。食物製品という用語は、本明細書で使用する場合、飲料をも包含する。
添加物として組成物を組み込める食物製品の例としては、スナック棒、シリアル、菓子及び生菌配合物、例えばヨーグルトが挙げられる。飲料の例としては、ソフト飲料、アルコール飲料、エネルギー飲料、乾燥飲料ミックス、栄養飲料及び注入用の薬草茶又は水で煎じて飲む薬草ブレンドが挙げられる。
The composition may be in the form of a solid composition or in the form of a liquid composition or gel. Suitable solid forms of the composition include a stick or a powder suitable for mixing with a liquid such as water, milk or fruit juice at the time of use. Suitable forms of liquid composition include, for example, syrups, emulsions and suspensions. Suitably, in the form of a syrup, the composition may further contain as carrier, for example, saccharose or saccharose and glycerin and / or mannitol and / or sorbitol. In the form of a suspension or emulsion, the composition may contain as a carrier, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
The composition can be a food product, food supplement, dietary supplement, functional food or dietary supplement or component thereof.
A food product is used in the body of an organism to sustain growth, repair damage, assist in life processes or provide energy, and is an edible product that is primarily composed of one or more macronutrient proteins, carbohydrates and fats It is a substance. The food product may also contain one or more micronutrients such as vitamins or minerals, or additional dietary ingredients such as seasonings and colorants. The term food product as used herein also encompasses beverages.
Examples of food products that can incorporate the composition as an additive include snack bars, cereals, confectionery and live fungal formulations such as yogurt. Examples of beverages include soft drinks, alcoholic drinks, energy drinks, dry drink mixes, nutritional drinks and herbal blends drunk with water or infused with herbal tea or water for injection.
栄養補助食品は、疾患の予防と治療を含めた医学的又は健康的利益を与えるとみなされる食物成分、食物サプリメント又は食物製品である。一般に栄養補助食品は消費者に特定の健康的利益を与えるように明確に適応している。栄養補助食品は典型的にビタミン、ミネラル、薬草又は植物化学物質等の微量栄養素を対応する普通の食物製品で見られるであろうより高いレベルで含む。当該レベルは典型的に、栄養補助食品を単一サービングとして又は栄養療法の食事計画若しくは過程の一部として摂取したときに意図した健康上の利益を最適化するように選択される。
機能性食品は、消費者に純粋な栄養素を供給するという利益を超えて健康上の利益を与えるとして市販されている食品である。機能性食品は典型的に、栄養学的効果以外の特定の医学的又は生理学的利益を与える上記微量栄養素等の成分を組み入れる。機能性食品は典型的に包装に健康強調表示を有している。
Nutritional supplements are food ingredients, food supplements or food products that are considered to provide medical or health benefits including prevention and treatment of disease. In general, dietary supplements are specifically adapted to provide consumers with specific health benefits. Nutritional supplements typically contain micronutrients such as vitamins, minerals, herbs or phytochemicals at higher levels than would be found in corresponding ordinary food products. The level is typically selected to optimize the intended health benefits when the dietary supplement is taken as a single serving or as part of a nutritional diet plan or process.
Functional foods are foods that are marketed as providing health benefits beyond the benefit of providing consumers with pure nutrients. Functional foods typically incorporate ingredients such as the micronutrients described above that provide specific medical or physiological benefits other than nutritional effects. Functional foods typically have health claims on the packaging.
本発明はさらなる態様で本発明のケトン体、ケトン体エステル及び組成物から選択される製品と、ケトンモニターと、任意的であるが所定レベルの血漿ケトンを達成するために単位体重当たり消費する製品のレベル及び血漿ケトンを所定レベルで維持して筋パワー出力を維持又は改善するための投与計画に関する説明書とを含んでなるキットを提供する。使用者は適切に製品を消費してから定期的に自らの血漿ケトンレベルを検査して、所望の血漿ケトンレベルを達成又は維持するためにケトンのさらなる摂取が必要かどうかを判断することができる。
好適にはケトン体若しくはケトン体エステル又はそれを含む組成物は消費についての説明書と共に提供される。適宜説明書により、1日当たり1以上の用量の本発明のケトン体若しくはケトン体エステル又はそれを含む組成物を消費するか或いは運動前、好ましくは運動の少なくとも10分、さらに好ましくは少なくとも30分、最適には少なくとも1時間前に用量を消費する。
例えば20分を超える持続性運動では、2以上の用量、さらに好ましくは2〜8用量、例えば3〜6用量を定期的に消費して血漿ケトンレベルを上昇させるか又は上昇した血漿ケトンレベルを維持することができる。使用者は血液をケトンで「刺激する」ようにパワー出力を維持又は改善するための用量を消費してよいが、規則的間隔で用量を消費するとさらに高いレベルの血中ケトン含量を維持するので適している。
以下の非限定例を参照することにより本発明を説明する。
The present invention in a further aspect, a product selected from the ketone bodies, ketone body esters and compositions of the present invention, a ketone monitor, and a product consumed per unit weight to achieve an optional but predetermined level of plasma ketone. And a dosage regimen for maintaining or improving plasma ketone and maintaining or improving muscle power output is provided. Users can properly test their plasma ketone levels after consuming the product properly to determine whether further intake of ketones is necessary to achieve or maintain the desired plasma ketone levels. .
Preferably a ketone body or ketone body ester or a composition comprising it is provided with instructions for consumption. If appropriate, consume one or more doses of the ketone body or ketone body ester of the present invention or a composition comprising the same per day or before exercise, preferably at least 10 minutes, more preferably at least 30 minutes before exercise, Optimally consume the dose at least one hour before.
For sustained exercise, eg greater than 20 minutes, consume 2 or more doses, more preferably 2-8 doses, eg 3-6 doses, to increase plasma ketone levels or maintain elevated plasma ketone levels can do. Users may consume doses to maintain or improve power output to “stimulate” blood with ketones, but consuming doses at regular intervals will maintain a higher level of blood ketone content. Is suitable.
The invention is illustrated by reference to the following non-limiting examples.
実施例1
方法：
対象及び募集
国家試験のGB漕艇により定義される資格基準によりアスリートを募集した。全ての体重分類の男女の両アスリートを試験に含め、サブエリート又はエリート力量のアスリートを募集するためにあらゆる努力をした。全てのアスリートは医学的疾患の前歴がなく、健康であった。アスリートは試験前に少なくとも12週間持続的に訓練し、全てのアスリートは、自らの訓練及び競技スケジュール内で規則的にこれらの試験を行なった。参加に伴うリスクの説明後に全てのアスリートから書面によるインフォームドコンセントを得た。全ての試験はヘルシンキ宣言で概説された倫理綱領の基準に従った。
いずれの運動試験前にもベースラインの医学的アンケート、身体検査、体組成分析及びECGを行なった。ベースラインの血液検査を行なって、能力に影響し得る鉄欠乏、Hb、電解質、WCC及び空腹時血糖等の他の可能性のある医学的原因を排除した。
Example 1
Method:
Target and Recruitment Athletes were recruited according to the qualification criteria defined by GB rowing boats in the national examination. Both male and female athletes of all weight categories were included in the study and every effort was made to recruit sub-elites or elite competent athletes. All athletes were healthy with no previous medical illness. Athletes trained continuously for at least 12 weeks prior to testing, and all athletes conducted these tests regularly within their training and competition schedule. Written informed consent was obtained from all athletes after explaining the risks involved. All trials followed the Code of Ethics outlined in the Declaration of Helsinki.
Baseline medical questionnaires, physical examination, body composition analysis and ECG were performed prior to any exercise test. Baseline blood tests were performed to eliminate other possible medical causes such as iron deficiency, Hb, electrolytes, WCC and fasting blood glucose that could affect performance.
表1：身体的特徴
HWM：重量男性；LWMN：軽量男性；HWW：重量女性；LWW：軽量女性
Table 1: Physical characteristics
HWM: Heavy male; LWMN: Light male; HWW: Heavy female; LWW: Light female
実験設計及び能力試験：
対象は少なくとも8時間の夜間絶食後にOxfordのJohn Radcliffe病院のOCMR部門に現れた。能力に及ぼす日周パターンの影響を減らすため日の同一時刻に試験を行なった。主要競技会前に消費するであろうように、前夜に同一の試験前食事を消費し、かつ毎来診前にこれを繰り返すようにアスリートに頼んだ。各試験の前48時間は激しい運動を行なわず、かつ24時間はアルコールを控えるようにアスリートに頼んだ。同じ3カ月以上(macrocycle)の訓練内でアスリートを確実に試験し、かつ訓練週内の試験のタイミングを統一するようにあらゆる努力をした。
Experimental design and performance test:
Subject appeared in the OCMR department of John Radcliffe Hospital in Oxford after at least 8 hours of night fast. Tests were conducted at the same time of the day to reduce the influence of diurnal patterns on performance. The same pre-study meal was consumed the night before, as would be consumed before the main competition, and the athletes were asked to repeat this before every visit. Forty-eight hours before each test, athletes were asked not to exercise vigorously and to refrain from alcohol for 24 hours. Every effort was made to ensure that athletes were tested within the same macrocycle of training and to unify the timing of the testing within the training week.
図1は、各試験日のプロトコルの概要を示し、飲料摂取、採血及び能力試験の時点を示している。プラセボ及び活性飲料についてこのプロトコルを繰り返した。
到着したら対象の体重を量り、対象の体組成を記録した後に試験施設の個室に対象を案内した。参加者は、体重調整した用量の飲料を5分にわたって摂取し、摂取後30分及び1時間の毛細管採血以外は60分間平静のままにした。
コンセプトIIローイングエルゴメーター(Model D, Nottingham, UK)を用いて全ての能力試験を行なった。参加者は全て毎日の訓練の一部としてこの試験装置を使用し、この装置の習熟を必要としなかった。注意散漫することなく、自由な空気の流れを受けやすいプライベートな領域で試験を行なった。全ての試験を17〜22℃の周囲条件で行ない、床置き型ファンでさらに冷やして熱的ストレスを最小限にした。各機会に同じ治験担当医師の存在下で個々にアスリートを試験した。要請があれば言葉による激励を行ない、そうでなければ無言で試験を行なった。アスリートが音楽を要求した場合、両試験で同一のプレイリストを確保した。運動完了の30秒以内に全ての毛細管血液サンプルを得た。
能力データを自動収集し、コンセプトIIエルゴメーター(PM3デバイス)に保管し、30分の試験中に5分間隔で、又は2km試験中に500m間隔でオフロードした。データをデータチップに保管し、解析のため研究用ノートパソコンに移した。残りの時間又は距離と共にリアルタイムデータをアスリート前のスクリーンに表示してストローク速度の順守を確実にし、500mのスプリットタイムをも表示した。アスリートがペーシングボート機能を用いることを禁止した。
FIG. 1 shows an overview of the protocol for each test day and shows the time points for beverage intake, blood sampling and performance testing. This protocol was repeated for placebo and active beverage.
Upon arrival, the subject was weighed and the subject's body composition was recorded before the subject was guided to a private room at the test facility. Participants ingested weight-adjusted doses over 5 minutes and remained calm for 60 minutes except for 30 minutes and 1 hour of capillary blood collection after ingestion.
All ability tests were performed using a Concept II rowing ergometer (Model D, Nottingham, UK). All participants used the test device as part of their daily training and did not require proficiency with the device. The test was conducted in a private area that was susceptible to free air flow without distraction. All tests were conducted at ambient conditions of 17-22 ° C. and were further cooled with a floor-standing fan to minimize thermal stress. At each opportunity, athletes were individually tested in the presence of the same investigator. If requested, verbal encouragement was given, otherwise the test was done silently. When an athlete requested music, they secured the same playlist in both tests. All capillary blood samples were obtained within 30 seconds of exercise completion.
Capability data was automatically collected and stored on a Concept II ergometer (PM3 device) and offloaded at 5 minute intervals during a 30 minute test or at 500 m intervals during a 2 km test. The data was stored on a data chip and transferred to a research laptop for analysis. Real-time data along with the remaining time or distance was displayed on the pre-athlete screen to ensure compliance with stroke speed and a 500m split time was also displayed. Athletes are prohibited from using the pacing boat function.
飲料の調製と投与：
各アスリートは、フードブレンダー内で2分間1:1.5部の比で水と混合した2.083g/kg(体重)の生飲料粉末を受けた。この活性ケトン飲料は、数日の総絶食に等価な、3mMのβ-ヒドロキシ酪酸のピークケトン血を達成するように計算した用量で生ケトンエステルを含む(R)-3-ヒドロキシ酪酸(R)-1,3-ブタンジオールモノエステルを含有した。プラセボ飲料はケトンと味、粘度及び色が同一であり、プラセボ製剤ではケトンの発熱当量を長鎖トリグリセリドで置き換えた。粉末としてのミルクセーキの(%乾燥質量)組成は以下のとおりだった：炭水化物45%、ケトン30%、タンパク質20%、及び脂肪(活性飲料では5%、プラセボでは35%)。全ての対象に盲検法で飲料を割り当て、5分の時間間隔で飲料を消費させ、その後対象を60分間安静にして消化させ、胃部不快感を最小限にした。
図2は、研究飲料の百分率組成を示す。活性飲料はケトンモノエステルを含有し、プラセボは同一組成の炭水化物とタンパク質を含有した。プラセボ飲料ではケトンモノエステル由来のカロリーを脂肪で置き換えた。
採血：1
動脈血化フィンガープリック(arterialised finger prick)(Accu-chekTM)によって毛細管血液サンプル(10〜50μL)を得、即座にハンドヘルド(handheld)モニター(Optium Xceed(登録商標), Abbott, UK and lactate Pro, Arkray, Japan)を用いてグルコース、ケトン及びラクトースについて分析した。
安静時ケトンのキネティクス：
血中ケトン濃度のプロファイルに及ぼす運動の効果を評価するため、血中ケトン濃度の安静時対運動時の変化を比較できるようにn=7の代表的年齢及び性別対応アスリート対照(n=6の男性及びn=1の女性)を選択して安静坐位状態中にケトン含有飲料の同一の投与及び吸収レジメを受けさせた。
Beverage preparation and administration:
Each athlete received 2.083 g / kg (body weight) of raw beverage powder mixed with water in a ratio of 1: 1.5 parts for 2 minutes in a food blender. This active ketone beverage contains raw ketone ester (R) -3-hydroxybutyric acid (R) at a dose calculated to achieve a peak ketone blood of 3 mM β-hydroxybutyric acid, equivalent to a total fast of several days 1,3-butanediol monoester was contained. Placebo beverages had the same taste, viscosity, and color as ketones, and the placebo formulation replaced the exothermic equivalent of ketones with long chain triglycerides. The composition (% dry weight) of the milkshake as a powder was as follows: 45% carbohydrate, 30% ketone, 20% protein, and fat (5% for active drinks, 35% for placebo). All subjects were assigned a beverage in a blinded manner, consuming the beverage at 5 minute time intervals, after which the subject was rested and digested for 60 minutes to minimize stomach discomfort.
FIG. 2 shows the percentage composition of the research beverage. The active beverage contained a ketone monoester and the placebo contained the same composition of carbohydrate and protein. In the placebo beverage, the calorie derived from the ketone monoester was replaced with fat.
Blood collection: 1
Arterialized finger prick (arterialised finger prick) (Accu- chek TM) to obtain a capillary blood sample (10~50μL) by immediately handheld (handheld) monitor (Optium Xceed (TM), Abbott, UK and lactate Pro , Arkray , Japan) for glucose, ketone and lactose.
Resting Ketone Kinetics:
To assess the effect of exercise on blood ketone concentration profiles, n = 7 representative age and gender-matched athlete controls (n = 6) were compared so that changes in blood ketone concentration during rest versus exercise could be compared. Males and n = 1 females) were selected to receive the same administration and absorption regimen of ketone-containing beverages during the sitting position.
統計：
対応スチューデントt検定(両側)を利用して能力結果(mでの距離、及び2km試験を完了するための秒数)を解析した。運動対対照の血中ケトンキネティクスの比較を二元配置反復測定ANOVAで行ない、ボンフェローニポストホック補正(Bonferroni Post hoc correction)を用いて有意な効果を解析した。
SPSS(Version 17, Chicago, IL)を用いてデータ評価を行ない、統計的有意性をp<0.05レベルに設定した。全てのデータを平均±平均の標準誤差として表し、30分試験ではn=22の統合平均、2km時間試験ではn=13の統合平均を示す。
全部で2名の対象を全解析から除外した。介入性疾患に基づいて1名の参加者を排除し、30分試験中の嘔吐とその後の試験装置による機械的干渉のため別の参加者を排除した。含めても結果は研究のいずれのポジティブ又はネガティブな知見をも変えないであろう。
これらの試験の結果を図3〜9に示す。
図3は、プラセボに対する個人の能力プロファイルを示す(%として表す)。WRは世界記録能力、PBはパーソナルベスト能力、SBはシーズンベスト能力である。
図4は、体重分類のサブグループ別の30分試験についてプラセボに対する能力効果を示す(%として表す)。**統合効果p<0.001。データは平均±SEとして表してある。
図5は、30分試験にわたるパワー出力と、プラセボに比べて骨格筋パワー出力を改善する際のケトンの有利な効果とを示す。
図6は、30分試験中の、時間試験の完了した1/3について統合したパワー出力を示す。試験の最初の10分後にプラセボ飲料に対してケトン群に有意差が観察された。データは平均±SEとして表してある。
図7は、各運動試験の持続時間にわたるケトンの血中レベルの変化を示す。ケトンの摂取は、プラセボに比べて血中β-OH酪酸濃度の顕著な上昇をもたらした(*全ての時点についてp<0.0001)。ケトン濃度は、運動前値に比べて運動試験の最後に顕著に低下した(# p<0.0001)。運動中、運動を行なわない安静対照対象と比べてケトン濃度は有意に低下した(α p<0.001)。
図8は、0.5g/kg(体重)のケトンの摂取前及び摂取後90分間の15分毎の血漿遊離脂肪酸濃度の変化を示す(n=4の対象)。
図9は、0.5g/kg(体重)のケトンの摂取前及び摂取後60分の血漿遊離脂肪酸濃度を示す(4名の対象)。
statistics:
The performance results (distance in m and number of seconds to complete the 2km test) were analyzed using paired student t-test (two-sided). Comparison of exercise versus control blood ketone kinetics was performed with two-way repeated measures ANOVA, and significant effects were analyzed using Bonferroni Post hoc correction.
Data evaluation was performed using SPSS (Version 17, Chicago, IL), and statistical significance was set at the p <0.05 level. All data are expressed as mean ± standard error of the mean, with n = 22 integrated average for the 30 minute test and n = 13 integrated average for the 2 km time test.
A total of 2 subjects were excluded from all analyses. One participant was excluded based on the interventional disease, and another participant was excluded due to vomiting during the 30-minute study and subsequent mechanical interference with the testing device. Including the results will not change any positive or negative findings of the study.
The results of these tests are shown in FIGS.
FIG. 3 shows an individual's ability profile for placebo (expressed as%). WR is the world record ability, PB is the personal best ability, and SB is the best season ability.
FIG. 4 shows the potency effect on placebo (expressed as%) for the 30-minute study by weight classification subgroup. ** Integration effect p <0.001. Data are expressed as mean ± SE.
FIG. 5 shows the power output over a 30 minute test and the beneficial effects of ketones in improving skeletal muscle power output compared to placebo.
FIG. 6 shows the integrated power output for 1/3 of the time test completed during the 30 minute test. Significant differences were observed in the ketone group for placebo beverages after the first 10 minutes of the study. Data are expressed as mean ± SE.
FIG. 7 shows the change in blood levels of ketones over the duration of each exercise test. Intake of ketones resulted in a significant increase in blood β-OH butyrate levels compared to placebo ( * p <0.0001 for all time points). The ketone concentration was significantly reduced at the end of the exercise test compared to the pre-exercise value (# p <0.0001). During exercise, the ketone concentration was significantly reduced compared to resting subjects who did not exercise (α p <0.001).
FIG. 8 shows the change in plasma free fatty acid concentration every 15 minutes before and 90 minutes after ingestion of 0.5 g / kg (body weight) of ketones (n = 4 subjects).
FIG. 9 shows plasma free fatty acid concentrations before and after ingestion of 0.5 g / kg (body weight) of ketones (4 subjects).
実施例2
多量体ケトンの血液中への取り込みを測定するための手順を行なった。0.1〜0.2mMの(R)-3-ヒドロキシ酪酸の血中レベルが観察され、生理学的に重大な関わりのある反応をもたらさないようであった。R-1,3-ブタンジオール-トリオリドジエステルは約1.5mMのピークレベルをもたらした。R-1,3ブタンジオール(R)-3-ヒドロキシ酪酸モノエステルは6mMのピーク血中レベルをもたらした。
これらの試験から下記結論を導き出すことができた。
1) 6〜7量体範囲の水溶性直鎖多量体は血中bHBの最小限の上昇しかもたらさない。
2) 8〜9量体範囲の固体の水不溶性直鎖多量体は6時間にわたって血中bHBを0.18mMに上昇させた。
3) どの直鎖多量体も血中ケトンの生理学的に重大な関わりのある上昇を引き起さないようであり、短鎖多量体は胃毒性と関連する。
4) R-1,3-ブタンジオールジトリオリドエステルは機能的に7量体単位長であり、嫌悪を感じる味がする血中レベルをもたらす。
Example 2
A procedure for measuring the uptake of multimeric ketones into the blood was performed. Blood levels of 0.1-0.2 mM (R) -3-hydroxybutyric acid were observed and did not appear to result in a physiologically relevant response. R-1,3-butanediol-triolide diester resulted in a peak level of about 1.5 mM. R-1,3 butanediol (R) -3-hydroxybutyric acid monoester resulted in a peak blood level of 6 mM.
The following conclusions could be drawn from these tests.
1) Water-soluble linear multimers in the 6-7 mer range give only minimal rise in blood bHB.
2) Solid water-insoluble linear multimers in the 8-9 mer range increased blood bHB to 0.18 mM over 6 hours.
3) None of the linear multimers appear to cause a physiologically relevant increase in blood ketones, and short chain multimers are associated with gastric toxicity.
4) R-1,3-butanediol ditriolide ester is functionally a 7-mer unit length, resulting in a blood level that tastes disgusting.
実施例3
種々のケトン体の風味を試験した。8名のテイスターのテイスティングパネルによって約100マイクロリットルの体積のケトン体を試験した。ケトンの風味を定性的基礎に基づいて評価してそれらの苦味を評価した。下表2は、試験したケトン体を示し、これらのケトンの構造を図10に示す。
Example 3
The flavor of various ketone bodies was tested. A ketone body with a volume of about 100 microliters was tested by a tasting panel of 8 tasters. The taste of ketones was evaluated on a qualitative basis to assess their bitterness. Table 2 below shows the ketone bodies tested and the structures of these ketones are shown in FIG.
表2−試験したケトン
Table 2-Tested ketones
試験の結果を下表3に示す。 The results of the test are shown in Table 3 below.
表3−結果
Table 3-Results
結果は以下のことを示す。
・それぞれ2及び3個の(R)-3-ヒドロキシ酪酸を有する多量体(ケトン1、3及び4)は全て苦いと認知され；
・特定単量体(ケトン2及び5)は苦いとみなされ、別の単量体(ケトン7)は苦くないが非常に不快であるとみなされた。これらの単量体はそれぞれテトラエステル、トリエステル及びジエステルであり；
・(R)-1,3-ブタンジオールのエステル(ケトン1及び4)は苦いとみなされ、(R)-1,3-ブタンジオールの別のエステル(ケトン7)は苦くないが非常に不快であるとみなされ、別のエステル(ケトン11)は許容できる風味を有し；
・(R)-1,3-ブタンジオールのモノエステル(ケトン4)は苦いと認知され；
・許容できる風味を有するケトンはケトン6及び8のみであり、それぞれグリセロールモノエステル及び(R)-1,3-ブタンジオールのモノエステルであった。
これらの試験を行なう前には多数の変量(酪酸基の数、アルコールのタイプ、エステル結合の数、特定アルコールの様々なエステル)の考慮に基づいてエステルの苦味の欠如は予測できなかった。結果でさえ、これらの要因の影響が混ざっている。試験したエステルの多量体は全て苦く(より長い鎖のヒドロキシ酪酸は苦味が低減し得るが)、苦いモノエステルもあるが、苦くないモノエステルもあり、(R)-1,3-ブタンジオールのエステルには苦いものがあり、1種のエステルは許容性であり、異なるアルコールのエステルは許容できる風味を有した。
The results show the following:
The multimers (ketones 1, 3 and 4) with 2 and 3 (R) -3-hydroxybutyric acid, respectively, are all recognized as bitter;
• Certain monomers (ketones 2 and 5) were considered bitter and another monomer (ketone 7) was not bitter but considered very uncomfortable. These monomers are tetraesters, triesters and diesters, respectively;
Ester of (R) -1,3-butanediol (ketones 1 and 4) is considered bitter and another ester of (R) -1,3-butanediol (ketone 7) is not bitter but very uncomfortable And another ester (ketone 11) has an acceptable flavor;
The monoester of (R) -1,3-butanediol (ketone 4) is recognized as bitter;
The only ketones with acceptable flavor were ketones 6 and 8, which were glycerol monoester and (R) -1,3-butanediol monoester, respectively.
Prior to conducting these tests, the lack of ester bitterness could not be predicted based on consideration of a number of variables (number of butyric acid groups, type of alcohol, number of ester linkages, various esters of a specific alcohol). Even the results are mixed effects of these factors. All of the ester multimers tested are bitter (although longer chain hydroxybutyric acid can reduce bitterness), some are bitter monoesters, but some are not bitter, and (R) -1,3-butanediol Some of the esters were bitter, one ester was acceptable, and esters of different alcohols had an acceptable flavor.
実施例4
種々のケトンの投与後にラット内の血中(R)-3-ヒドロキシ酪酸濃度を決定するための実験を行なった。試験したケトンを下表4に示す。ケトンは上記ケトン1〜8と同様の味がした。
10mlの水に表3に示す2gのケトンを含むサワークリームミックスをそれぞれラットに与えた。餌を与える直前、餌を与えた後1時間、3時間及び6時間に各ラットから血液サンプルを取って(R)-3-ヒドロキシ酪酸の血中濃度を測定した。ケトンを添加しない同一ミックスを与えることによって2匹の対照(対照A及び対照B)をも試験した。人道的にラットを殺し、目視検査のため解剖して幽門狭窄又は他の可視変化が起こったかどうかを判断した。
血液を抽出し、0.1mlの全血を0.4mlの3.6%過塩素酸に加えてボルテックスに供してから氷内で30分間静止させてから回転させた。次に350ulの酸性上清を新たなチューブに移し、5ulのフェノールレッド(0.05%)、20ulの1MイミダゾールpH7及び3M KHCO3を加えて溶液を中和し、氷内に30分間放置してから回転させた。次に中和血液抽出物のサンプルを(R)-3-ヒドロキシ酪酸についてアッセイした。試験したケトンを下表4に示す。
Example 4
An experiment was conducted to determine the blood (R) -3-hydroxybutyric acid concentration in rats after administration of various ketones. The tested ketones are shown in Table 4 below. The ketone tasted the same as ketones 1-8 above.
Rats were given a sour cream mix containing 2 g of the ketone shown in Table 3 in 10 ml of water. Blood samples were taken from each rat immediately before feeding, 1 hour, 3 hours and 6 hours after feeding to determine the blood concentration of (R) -3-hydroxybutyric acid. Two controls (Control A and Control B) were also tested by giving the same mix with no added ketone. Rats were humanely killed and dissected for visual inspection to determine if pyloric stenosis or other visible changes occurred.
Blood was extracted, 0.1 ml whole blood was added to 0.4 ml 3.6% perchloric acid, vortexed, allowed to rest in ice for 30 minutes and then rotated. The 350ul acidic supernatant is then transferred to a new tube, neutralized by adding 5ul phenol red (0.05%), 20ul 1M imidazole pH7 and 3M KHCO 3 and left in ice for 30 minutes. Rotated. Samples of neutralized blood extract were then assayed for (R) -3-hydroxybutyric acid. The tested ketones are shown in Table 4 below.
表4-ケトン
Table 4-Ketones
これらの実験の結果を下表5に示す。 The results of these experiments are shown in Table 5 below.
表5−結果
Table 5-Results
各ケトンの投与に由来する(R)-3-ヒドロキシ酪酸の濃度をプロットし、図11に示す。
これらの実験の結果は以下のことを示している。
・3〜8、5〜7及び8〜10量体範囲の多量体(ケトン9、11及び12)は、0.1〜0.2mMの(R)-3-ヒドロキシ酪酸血中レベルをもたらし、生理学的に重大な関わりのある反応を引き起こさないようであり；
・ケトン10(R-1,3-ブタンジオールトリオリドジエステル)は約1.5mMのピークレベルを生じさせたが、嫌悪風味を有し；
・本発明のケトン13(上記ケトン8と同じ)は6mMのピーク血中レベルをもたらし；
・ケトン9(8〜10量体)では、生じたラット糞が黄色であり、これはケトンが分解されずに腸を横断したか又は重大な程度まで血液中に取り込まれたことを示唆しており；
・より短い鎖の多量体は有意な急性胃毒性に関連する。
ケトン9〜13の構造の考慮に基づくと、ケトンの取り込みは予測できなかった。長鎖多量体は無味であり、急性胃毒性の徴候を示さなかったが、生理学的に重大な関わりのある程度には血中に取り込まれなかった。短鎖多量体も重大な程度まで取り込まれず、嫌悪を感じる味がし、急性胃毒性を引き起こした。(R)-1,3-ブタンジオールのトリオリドジエステル(ケトン10)は、生理学的反応をもたらし得る取り込みレベルを示し、この取り込みレベルは試験した他の多量体のレベルの約10倍であった。しかしながら、このケトンは嫌悪を感じる味がした。
ケトン8/13((R)-3-ヒドロキシ酪酸-(R)-1,3-ブタンジオール)は、試験した直鎖多量体(ケトン9、11及び12)の血液への取り込みレベルの30〜40倍及びトリオリドジエステル多量体(ケトン10)の約4倍である血液への取り込みレベルを示す。図11には、この取り込みレベルの非常に大きな差異をグラフにより示してあり、ケトン13の濃度は6mMに上昇する。
The concentration of (R) -3-hydroxybutyric acid derived from administration of each ketone is plotted and shown in FIG.
The results of these experiments show that:
-Multimers in the 3-8, 5-7 and 8-10 mer range (ketones 9, 11 and 12) give (R) -3-hydroxybutyric acid blood levels of 0.1-0.2 mM physiologically Does not appear to cause a significant and relevant reaction;
Ketone 10 (R-1,3-butanediol triolide diester) produced a peak level of about 1.5 mM but had an aversive flavor;
• Ketone 13 of the present invention (same as ketone 8 above) results in a peak blood level of 6 mM;
For ketone 9 (8-10 mer), the resulting rat feces is yellow, suggesting that the ketone has crossed the intestine without being broken down or taken into the blood to a significant degree There;
• Short chain multimers are associated with significant acute gastric toxicity.
Based on the structural considerations of ketones 9-13, ketone uptake could not be predicted. Long chain multimers were tasteless and showed no signs of acute gastric toxicity, but were not taken up into the blood to some degree of physiological significance. Short-chain multimers were not taken up to a critical extent, tasted to be disgusted, and caused acute gastric toxicity. Triolide diester of (R) -1,3-butanediol (ketone 10) showed an uptake level that could result in a physiological response, which was about 10 times the level of other multimers tested . However, this ketone tasted disgusting.
Ketone 8/13 ((R) -3-hydroxybutyric acid- (R) -1,3-butanediol) has a blood uptake level of 30 to 30 of the tested linear multimers (ketones 9, 11, and 12). Shows blood uptake levels that are 40 times and about 4 times that of triolide diester multimer (ketone 10). FIG. 11 graphically illustrates this very large difference in uptake level, with the concentration of ketone 13 increasing to 6 mM.
実施例5
(R)-3-ヒドロキシ酪酸-R-1,3ブタンジオールモノエステルを数名の対象に対象の体重1kg当たり固定量に基づいて単一用量で投与した。一定期間にわたって血中(R)-3-ヒドロキシ酪酸濃度を測定して、経口単一用量と(R)-3-ヒドロキシ酪酸の血中濃度との間の用量／反応関係を決定した。この手順を様々な量の(R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオモノエステルで繰り返して、192mg/kg、291mg/kg、395mg/kg及び573mg/kgで投与したときの(R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオールモノエステルについての用量／反応関係についてのデータを提供した。
結果を図12にグラフを使って示してあり、単一用量の少量の(R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオールモノエステルが血中(R)-3-ヒドロキシ酪酸濃度を以前に他のケトンでは報告されていないレベルに上昇させることを実証しており、これはR-1,3-ブタンジオールの(R)-3-ヒドロキシ酪酸多量体で一般的に達成できるより桁違いに大きい。
次に、本発明の態様を示す。
1. 対象の筋パワー出力の維持又は改善に用いるためのケトン体又はケトン体エステル。
2. 骨格筋パワー出力の維持又は改善に用いるための、上記1に従って用いるケトン体又はケトン体エステル。
3. 前記対象が健康人である、上記1又は2に従って用いるケトン体又はケトン体エステル。
4. 本明細書の実施例で述べるように30分にわたって対照試験で測定すると、プラセボに対して少なくとも0.25%のパワー出力の改善をもたらす、上記1〜3のいずれか1項に従って用いるケトン体又はケトン体エステル。
5. 本明細書の実施例で述べるように30分にわたって対照試験で測定すると、プラセボに対して少なくとも1ワットのパワー出力の増加をもたらす、上記1〜4のいずれか1項に従って用いるケトン体又はケトン体エステル。
6. ケトンエステルである、上記1〜5のいずれか1項に従って用いるケトン体又はケトン体エステル。
7. ヒドロキシ酪酸及びその誘導体を含んでなる、上記1〜6のいずれか1項に従って用いるケトン体又はケトン体エステル。
8. ヒドロキシ酪酸エステル又は部分エステルを含んでなり、前記対象の血液中のヒドロキシ酪酸及びアセト酢酸の循環レベルが0mMから1mMより大きく5mMまでである、上記1〜7のいずれか1項に従って用いるケトン体又はケトン体エステル。
9. (R)-3-ヒドロキシ酪酸-R-1,3-ブタンジオールモノエステルを含んでなる、上記1〜8のいずれか1項に従って用いるケトン体又はケトン体エステル。
10. 対象の筋パワー出力の維持又は改善に用いるためのケトン体又はケトン体エステルを含んでなる組成物。
11. 水と、ケトン体又はケトン体エステルとを含み、任意に調味料、タンパク質、炭水化物、糖、脂肪、繊維、ビタミン及びミネラルの1種以上を含んでよい、上記10に記載の組成物。
12. 前記ケトン体又はケトン体前駆物質がケトンエステル及び／又は中鎖トリグリセリドを含む、上記10又は11に記載の組成物。
13. 前記組成物が、式CH 2 R 1 -CH 2 R 2 -CH 2 R 3 （式中、R 1 、R 2 及びR 3 は、5〜12個の炭素原子を有する脂肪酸である）を有する中鎖トリグリセリドを含む、上記12に記載の組成物。
14. ケトン体若しくはケトン体エステル又はケトン体若しくはケトン体エステルを含有する上記10又は11に記載の組成物の、対象の筋パワー出力の維持又は改善における使用。
Example 5
(R) -3-Hydroxybutyric acid-R-1,3 butanediol monoester was administered to several subjects in a single dose based on a fixed dose per kg of subject's body weight. The blood (R) -3-hydroxybutyric acid concentration was measured over a period of time to determine the dose / response relationship between the oral single dose and the blood concentration of (R) -3-hydroxybutyric acid. This procedure was repeated with various amounts of (R) -3-hydroxybutyric acid-R-1,3-butanediomonoester when administered at 192 mg / kg, 291 mg / kg, 395 mg / kg and 573 mg / kg. Data on the dose / response relationship for (R) -3-hydroxybutyric acid-R-1,3-butanediol monoester was provided.
The results are shown graphically in FIG. 12, where a single dose of a small amount of (R) -3-hydroxybutyric acid-R-1,3-butanediol monoester results in blood (R) -3-hydroxybutyric acid concentrations. Has been demonstrated to increase to levels not previously reported by other ketones, which is generally achievable with (R) -3-hydroxybutyric acid multimers of R-1,3-butanediol. An order of magnitude larger.
Next, the aspect of this invention is shown.
1. a ketone body or a ketone body ester for use in maintaining or improving the muscle power output of a subject.
2. A ketone body or a ketone body ester used according to the above 1 for use in maintaining or improving skeletal muscle power output.
3. A ketone body or a ketone body ester used according to 1 or 2 above, wherein the subject is a healthy person.
4. A ketone body used according to any one of paragraphs 1 to 3 above that results in an improvement in power output of at least 0.25% over the placebo when measured in a control test over 30 minutes as described in the examples herein. Ketone body ester.
5. A ketone body used according to any one of paragraphs 1 to 4 above, which results in an increase in power output of at least 1 watt relative to placebo when measured in a control test over 30 minutes as described in the examples herein. Ketone body ester.
6. A ketone body or a ketone body ester used according to any one of the above 1 to 5, which is a ketone ester.
7. A ketone body or a ketone body ester used according to any one of 1 to 6 above, comprising hydroxybutyric acid and a derivative thereof.
8. A ketone used according to any one of 1 to 7 above, comprising a hydroxybutyric acid ester or a partial ester, wherein the circulating level of hydroxybutyric acid and acetoacetic acid in the blood of the subject is from 0 mM to greater than 1 mM to 5 mM. Body or ketone body ester.
9. A ketone body or a ketone body ester used according to any one of 1 to 8 above, which comprises (R) -3-hydroxybutyric acid-R-1,3-butanediol monoester.
10. A composition comprising a ketone body or a ketone body ester for use in maintaining or improving the muscle power output of a subject.
11. The composition according to 10 above, comprising water and a ketone body or a ketone body ester, and optionally containing one or more of a seasoning, protein, carbohydrate, sugar, fat, fiber, vitamin and mineral.
12. The composition according to the above 10 or 11, wherein the ketone body or ketone body precursor comprises a ketone ester and / or a medium chain triglyceride.
13. The composition has the formula CH 2 R 1 —CH 2 R 2 —CH 2 R 3 , wherein R 1 , R 2 and R 3 are fatty acids having 5 to 12 carbon atoms. 13. The composition of claim 12, comprising a medium chain triglyceride having.
14. Use of a ketone body or a ketone body ester or a composition according to the above 10 or 11 containing a ketone body or a ketone body ester in maintaining or improving the muscle power output of a subject.
Claims (11)
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| GB1206192.5 | 2012-04-05 | ||
| PCT/EP2013/057250 WO2013150153A1 (en) | 2012-04-05 | 2013-04-05 | Ketone bodies and ketone body esters for maintaining or improving muscle power output |
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| JP2015514104A JP2015514104A (en) | 2015-05-18 |
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| CA2873092C (en) | 2020-08-04 |
| EP2833882B1 (en) | 2019-07-24 |
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| CA2873092A1 (en) | 2013-10-10 |
| ES2748050T3 (en) | 2020-03-12 |
| AU2013244931B2 (en) | 2018-01-18 |
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